The Differential Expression of Apoptosis Factors in the Alveolar Epithelium Is Redox Sensitive and Requires NF-κB (RelA)-Selective Targeting

John J. E. Haddad, Stephen C. Land

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Fetal alveolar type II (fATII) epithelial cells were used to evaluate the role of signaling factors involved in oxidative stress-induced programmed cell death (PCD; apoptosis). Bcl-2, an antiapoptotic proto-oncogene, showed maximum abundance in hypoxia and mild reoxygenation, but declined thereafter. The Bcl-2 counterpart, Bax, which promotes PCD, displayed an increasing log arithmic profile with ascending ΔpO2 regimen, such that the ratio of Bcl-2/Bax decreased as pO2 increased. The expression of p53, a cell cycle regulator, paralleled Bax abundance. Pretreatment of fATII cells with L-buthionine-(S,R)-sulfoximine, an irreversible inhibitor of γ-glutamylcysteine synthetase, the rate-limiting enzyme in the biosynthesis of glutathione (GSH), enhanced Bax and p53 expression over Bcl-2. The GSH analogue, γ-glutamylcysteinyl-ethyl ester, down-regulated Bax/p53 abundance but restored that of Bcl-2, thereby increasing Bcl-2/Bax. The antioxidant and GSH precursor N-acetyl-L-cysteine favored Bcl-2 at the expense of Bax/p53, whereas pyrrolidine dithiocarbamate induced Bax against Bcl-2, with mild effect on p53. Sulfasalazine, a potent and specific inhibitor of NF-κB, induced Bax at the expense of Bcl-2, in a p53-dependent manner. We conclude that the differential expression of signaling factors involved in PCD in the alveolar epithelium is redox-sensitive and mediated, at least in part, by a negative feedback mechanism transduced by NF-κB. (C) 2000 Academic Press.

Original languageEnglish
Pages (from-to)257-267
Number of pages11
JournalBiochemical and Biophysical Research Communications
Volume271
Issue number1
DOIs
Publication statusPublished - 29 Apr 2000

Keywords

  • Apoptosis
  • Glutathione
  • N-acetyl-L-cysteine
  • NF-κB (RelA/p65)
  • Pyrrolidine dithiocarbamate
  • Redox equilibrium
  • Sulfasalazine

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